Optimizing Allogeneic Hematopoietic Cell Transplantation for Older Patients with Hematologic Malignancies

优化老年血液恶性肿瘤患者的同种异体造血细胞移植

• 批准号: 10518677
• 负责人: Shannon Rose McCurdy
• 金额: $ 16.25万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10518677
• 关键词: Aging; Allogenic; Biological Markers; Blood; Blood Banks; Blood specimen; CD28 gene; Data; Dose; Elderly; Enrollment; Future; Gait speed; Geriatric Assessment; Hand Strength; Hematologic Neoplasms; Immune; Length; Lymphocyte; Measures; Methotrexate; Natural Killer Cells; Observational Study; Outcome; Patients; Phase I Clinical Trials; Phenotype; Population; Prophylactic treatment; Sampling; T-Lymphocyte; Tacrolimus; Toxic effect; Transplantation; Work; curative treatments; frailty; hematopoietic cell transplantation; improved; mortality; novel; older patient; phase I trial; prevent; programmed cell death protein 1; senescence; specific biomarkers; telomere; translational study

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are cancers of the blood and bone marrow that primarily occur in older adults (those 60 years and older).1 The incidence of these myeloid neoplasms increases with age, peaking beyond 75 years old.2 The overall incidence in the U.S. has been rising about 1.5% each year, reflective of an aging population. The only potentially curative treatment is allogeneic hematopoietic cell transplantation (HCT). HCT is physiologically stressful and associated with treatment-related mortality (TRM), which occurs in 10-20% of young and healthy patients and in up to 40-50% of older patients with comorbidities. 3•4 We have seen a remarkable expansion in the number of older patients receiving HCT due to the development of reduced intensity conditioning (RIC) approaches. In 2000, patients over 60 represented <5% of transplant recipients, whereas in 2018 they represented 39% of HCT recipients.5 Patients over 70 were almost never transplanted before 2007; in 2018 they made up 9% of HCT recipients. 5 Despite these trends, older patients, particularly those over 70, are often not offered HCT. 6 This creates a weighty disparity: those most affected by these devastating disease are least likely to be offered the cure. The recently FDA approved combination of azacitidine and venetoclax results in a 68% complete remission (CR) rate for patients over the age of 70 with newly diagnosed AML, 7 whereas the prior standard-of-care (SOC) therapy in this age group seldom did. The availability of a highly effective induction for this age group necessitates innovation in HCT since (1) induction is not curative, with relapse occurring at a median of 12 months, (2) SOC HCT has a 5-year overall survival (OS) of only 29% in older patients,8 and (3) patients over 75 years old are excluded from SOC HCT. To understand the impact of SOC HCT recipients~ 60 years old, we measured geriatric parameters as part of the Frailty Study, which forms the preliminary data for this grant. Patients who were deemed fit according to Fried's frailty phenotype (FP) enjoyed a 2- year TRM of 12%, compared with 30% and 47% in pre-frail and frail recipients, respectively. 24 In addition, 66% of patients had a decline in their frailty phenotype at Day 30 post-HCT and 90% of patients were pre-frail or frail at this time point. This highlights that there is an unmet need for less toxic HCT strategies for older recipients. Graft-vs-host disease (GVHD) is one of the most significant complications after HCT and a leading cause of morbidity and mortality. Post-transplantation cyclophosphamide (PTCy) is a revolutionary GVHD prevention strategy that was pioneered by one of my mentors, Dr. Luznik, and has replaced SOC GVHD prophylaxis strategies for HLA-mismatched transplantation, in part due to my work9-17 and that of my collaborator on this project (Dr. Kanakry). 18-23 This project aims to expand the use of PTCy beyond HLA-mismatched transplantation, reducing the dose to allow safe HCT of older or prefrail/ frail recipients. Analyses will also be performed to explore the effects of HCT on biomarkers of aging. Dr. Kanakry is the laboratory scientist lead and I am the clinical scientist lead on this phase 1 clinical trial (OPTCy, NCT04959175) that is now open at its two sites: The National Cancer Institute and The University of Pennsylvania.

急性骨髓性白血病（AML）和骨髓增生异常综合征（MDS）是血液和骨髓的癌症， 主要发生在老年人（60岁及以上）。1这些骨髓肿瘤的发病率随年龄增加， 75岁以后达到高峰。2美国的总体发病率每年上升约1.5%，反映了 人口老龄化唯一可能治愈的治疗是异基因造血细胞移植（HCT）。HCT是 生理压力并与治疗相关死亡率（TRM）相关，发生在10-20%的年轻人和 健康患者和高达40-50%的患有合并症的老年患者。3·4我们已经看到了一个显着的扩张， 由于降低强度预处理（RIC）方法的发展而接受HCT的老年患者数量。 2000年，60岁以上的患者占移植受者的5%，而2018年，他们占HCT的39% 在2007年之前，70岁以上的患者几乎从未接受过移植;在2018年，他们占HCT接受者的9%。5 尽管有这些趋势，老年患者，特别是70岁以上的患者，通常不提供HCT。6、这是一个沉重的 差距：受这些毁灭性疾病影响最严重的人最不可能得到治愈。 最近FDA批准的阿扎胞苷和维奈托克的组合导致68%的完全缓解（CR）率， 年龄超过70岁的新诊断AML患者，7而该年龄段的既往标准治疗（SOC）治疗 集团很少这样做。为该年龄组提供高效诱导需要HCT的创新，因为 (1)诱导治疗不能治愈，复发发生的中位时间为12个月，（2）SOC HCT的5年总生存期 (OS)仅29%的老年患者中，8例和（3）75岁以上的患者被排除在SOC HCT之外。了解 SOC HCT接受者的影响~ 60岁，我们测量了老年参数作为虚弱研究的一部分， 这份补助金的初步数据根据弗里德的虚弱表型（FP）被认为合适的患者享有2- 年TRM为12%，而虚弱前和虚弱接受者分别为30%和47%。24此外，66% 在HCT后第30天，患者的虚弱表型下降，90%的患者在该时间点处于虚弱前或虚弱 时间点。这突出表明，对于老年接受者来说，毒性较小的HCT策略的需求尚未得到满足。 移植物抗宿主病（GVHD）是HCT后最重要的并发症之一，也是导致发病和死亡的主要原因。 mortality.移植后环磷酰胺（PTCy）是一种革命性的GVHD预防策略， 由我的一位导师Luznik博士开创，并已取代HLA不匹配的SOC GVHD预防策略 移植，部分是由于我的工作9 -17和我的合作者在这个项目（Kanakry博士）。18-23本项目旨在 将PTCy的使用范围扩大到HLA不匹配的移植之外，减少剂量以允许老年人或体弱前期患者的安全HCT/ 虚弱的接受者。还将进行分析以探索HCT对衰老生物标志物的影响。卡纳克里博士 实验室科学家负责人，我是这项1期临床试验（OPTCy，NCT 04959175）的临床科学家负责人， 现在在两个地点开放：国家癌症研究所和宾夕法尼亚大学。